MiR-223-3p in Cancer Development and Cancer Drug Resistance: Same Coin, Different Faces.

MicroRNAs (miRNAs) are mighty post-transcriptional regulators in cell physiology and pathophysiology. In this review, we focus on the role of miR-223-3p (henceforth miR-223) in various cancer types. MiR-223 has established roles in hematopoiesis, inflammation, and most cancers, where it can act as either an oncogenic or oncosuppressive miRNA, depending on specific molecular landscapes.

Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance.

Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool.

Lmx1a-Dependent Activation of miR-204/211 Controls the Timing of Nurr1-Mediated Dopaminergic Differentiation.

The development of midbrain dopaminergic (DA) neurons requires a fine temporal and spatial regulation of a very specific gene expression program. Here, we report that during mouse brain development, the microRNA (miR-) 204/211 is present at a high level in a subset of DA precursors expressing the transcription factor Lmx1a, an early determinant for DA-commitment, but not in more mature neurons expressing Th or Pitx3. By combining different in vitro model systems of DA differentiation, we show that the levels of Lmx1a influence the expression of miR-204/211.

Nucleolar localization of the ErbB3 receptor as a new target in glioblastoma.

Background: The nucleolus is a subnuclear, non-membrane bound domain that is the hub of ribosome biogenesis and a critical regulator of cell homeostasis. Rapid growth and division of cells in tumors are correlated with intensive nucleolar metabolism as a response to oncogenic factors overexpression. Several members of the Epidermal Growth Factor Receptor (EGFR) family, have been identified in the nucleus and nucleolus of many cancer cells, but their function in these compartments remains unexplored.

Nucleolar stress controls mutant Huntington toxicity and monitors Huntington's disease progression.

Transcriptional and cellular-stress surveillance deficits are hallmarks of Huntington's disease (HD), a fatal autosomal-dominant neurodegenerative disorder caused by a pathological expansion of CAG repeats in the Huntingtin (HTT) gene. The nucleolus, a dynamic nuclear biomolecular condensate and the site of ribosomal RNA (rRNA) transcription, is implicated in the cellular stress response and in protein quality control. While the exact pathomechanisms of HD are still unclear, the impact of nucleolar dysfunction on HD pathophysiology in vivo remains elusive.

B55α/PP2A Limits Endothelial Cell Apoptosis During Vascular Remodeling: A Complementary Approach To Disrupt Pathological Vessels?

Rationale: How endothelial cells (ECs) migrate and form an immature vascular plexus has been extensively studied. Yet, mechanisms underlying vascular remodeling remain poorly established. A better understanding of these processes may lead to the design of novel therapeutic strategies complementary to current angiogenesis inhibitors.

Naive CD4 T Cells Carrying a TLR2 Agonist Overcome TGF-β-Mediated Tumor Immune Evasion.

TLR agonists are effective at treating superficial cancerous lesions, but their use internally for other types of tumors remains challenging because of toxicity. In this article, we report that murine and human naive CD4 T cells that sequester PamCys (CD4 T) become primed for T1 differentiation. CD4 T cells encoding the OVA-specific TCR OT2, when transferred into mice bearing established TGF-β-OVA-expressing thymomas, produce high amounts of IFN-γ and sensitize tumors to PD-1/programmed cell death ligand 1 blockade-induced rejection.

Identification of the zinc finger 216 (ZNF216) in human carcinoma cells: a potential regulator of EGFR activity.

Epidermal Growth Factor Receptor (EGFR), a member of the ErbB family of receptor tyrosine kinase (RTK) proteins, is aberrantly expressed or deregulated in tumors and plays pivotal roles in cancer onset and metastatic progression. ZNF216 gene has been identified as one of Immediate Early Genes (IEGs) induced by RTKs. Overexpression of ZNF216 protein sensitizes 293 cell line to TNF-α induced apoptosis.

The expression of B23 and EGR1 proteins is functionally linked in tumor cells under stress conditions.

Background: The nucleolus is a multi-domain enriched with proteins involved in ribosome biogenesis, cell cycle and apoptosis control, viral replication and differentiation of stem cells. Several authors have suggested a role for the nucleolus also in malignant transformation. We have recently demonstrated that under specific circumstances the transcriptional factor EGR1 is shuttled to the nucleolus where it functions as a negative regulator of RNA polymerase I.

The potential of GMP-compliant platelet lysate to induce a permissive state for cardiovascular transdifferentiation in human mediastinal adipose tissue-derived mesenchymal stem cells.

Human adipose tissue-derived mesenchymal stem cells (ADMSCs) are considered eligible candidates for cardiovascular stem cell therapy applications due to their cardiac transdifferentiation potential and immunotolerance. Over the years, the in vitro culture of ADMSCs by platelet lysate (PL), a hemoderivate containing numerous growth factors and cytokines derived from platelet pools, has allowed achieving a safe and reproducible methodology to obtain high cell yield prior to clinical administration. Nevertheless, the biological properties of PL are still to be fully elucidated.

Direct correlation between double K-RAS mutation and mucinous carcinoma. A case report.

Mutations at the K-RAS locus in colon cancer cells are frequently associated with lack of responsiveness to therapy with EGFR inhibitors, as a consequence of the activation of Ras-dependent intracellular signals. Here we report a colon cancer case carrying a novel combination of K-RAS mutations involving codon 13 (Gly to Asp) and codon 19 (Leu to Phe), on separate alleles. The double mutation was restricted to tumor cells bearing a mucinous-like phenotype.

M2muscarinic receptors inhibit cell proliferation and migration in urothelial bladder cancer cells.

The role of muscarinic receptors in several diseases including cancer has recently emerged. To evaluate the hypothesis that muscarinic acetylcholine receptors may play a role in bladder cancer as well as in other tumor types, we investigated their expression in bladder tumor specimens. All examined samples expressed the M1, M2 and M3 receptor subtypes.

The transcription factor EGR1 localizes to the nucleolus and is linked to suppression of ribosomal precursor synthesis.

EGR1 is an immediate early gene with a wide range of activities as transcription factor, spanning from regulation of cell growth to differentiation. Numerous studies show that EGR1 either promotes the proliferation of stimulated cells or suppresses the tumorigenic growth of transformed cells. Upon interaction with ARF, EGR1 is sumoylated and acquires the ability to bind to specific targets such as PTEN and in turn to regulate cell growth.

Altered calcium regulation in isolated cardiomyocytes from Egr-1 knock-out mice.

Early growth response-1 one gene (Egr-1), one of the immediate early response genes, plays an important role in the adaptive response of the myocardium to hypertrophic stimuli. We aimed to investigate the effects of Egr-1 deletion on cardiac function. Egr-1 knock-out (Egr-1(-/-)) homozygous mice were employed to evaluate the electrophysiological and molecular properties of left ventricular cardiomyocytes (VCM) by using patch-clamp technique, intracellular calcium measurements, real-time PCR, and Western blot.

Nucleolar localization and circadian regulation of Per2S, a novel splicing variant of the Period 2 gene.

In this work, we show for the first time that a second splicing variant of the core clock gene Period 2 (Per2), Per2S, is expressed at both the mRNA and protein levels in human keratinocytes and that it localizes in the nucleoli. Moreover, we show that a reversible perturbation of the nucleolar structure acts as a resetting stimulus for the cellular clock. Per2S expression and periodic oscillation upon dexamethasone treatment were assessed by qRT-PCR using specific primers.

M2 receptor activation inhibits cell cycle progression and survival in human glioblastoma cells.

Muscarinic receptors, expressed in several primary and metastatic tumours, appear to be implicated in their growth and propagation. In this work we have demonstrated that M2 muscarinic receptors are expressed in glioblastoma human specimens and in glioblastoma cell lines. Moreover, we have characterized the effects of the M2 agonist arecaidine on cell growth and survival both in two different glioblastoma cell lines (U251MG and U87MG) and in primary cultures obtained from different human biopsies.

The inhibition of KCa3.1 channels activity reduces cell motility in glioblastoma derived cancer stem cells.

In the present study we evaluated the expression of the intermediate conductance calcium-activated potassium (KCa3.1) channel in human glioblastoma stem-like cells (CSCs) and investigated its role in cell motility. While the KCa3.

Sensitivity to cisplatin in primary cell lines derived from human glioma correlates with levels of EGR-1 expression.

Background: Less than 30% of malignant gliomas respond to adjuvant chemotherapy. Here, we have asked whether variations in the constitutive expression of early-growth response factor 1 (EGR-1) predicted acute cytotoxicity and clonogenic cell death in vitro, induced by six different chemotherapics.

Materials And Methods: Cytotoxicity assays were performed on cells derived from fresh tumor explants of 18 human cases of malignant glioma.

A small sequence in domain v of the mitochondrial large ribosomal RNA restores Drosophila melanogaster pole cell determination in uv-irradiated embryos.

The mechanism by which the mitochondrial large rRNA is involved in the restoration of the pole cell-forming ability in Drosophila embryos is still unknown. We identified a 15-ribonucleotide sequence which is conserved from the protobacterium Wolbachia to the higher eukaryotes in domain V of the mitochondrial large rRNA. This short sequence is sufficient to restore pole cell determination in UV-irradiated Drosophila embryos.

The HIV Tat protein affects processing of ribosomal RNA precursor.

Background: Inside the cell, the HIV Tat protein is mainly found in the nucleus and nucleolus. The nucleolus, the site of ribosome biogenesis, is a highly organized, non-membrane-bound sub-compartment where proteins with a high affinity for nucleolar components are found. While it is well known that Tat accumulates in the nucleolus via a specific nucleolar targeting sequence, its function in this compartment it still unknown.

The HIV-Tat protein induces chromosome number aberrations by affecting mitosis.

To analyze the effects of the HIV-Tat-tubulin interaction, we microinjected HIV-Tat purified protein into Drosophila syncytial embryos. Following the Tat injection, altered timing of the cortical nuclear cycles was observed; specifically, the period between the nuclear envelope breakdown and anaphase initiation was lengthened as was the period between anaphase initiation and the formation of the next nuclear envelope. These two periods correspond to kinetochore alignment at metaphase and to mitosis exit, respectively.

An amphibian antimicrobial peptide variant expressed in Nicotiana tabacum confers resistance to phytopathogens.

Esculentin-1 is a 46-residue antimicrobial peptide present in skin secretions of Rana esculenta. It is effective against a wide variety of micro-organisms, including plant pathogens with negligible effects on eukaryotic cells. As a possible approach to enhance plant resistance, a DNA coding for esculentin-1, with the substitution Met-28Leu, was fused at the C-terminal end of the leader sequence of endopolygalacturonase-inhibiting protein, under the control of the cauliflower mosaic virus 35S promoter region, and introduced into Nicotiana tabacum.